{60 {8 3(R)-alkyl-4(R) piperidyl methyl{9 -{62 -(6,7 substituted-4 quinolyl)-2-alkanoyloxy propane and racemates

ABSTRACT

The preparation of quinine, quinidine, isomers and derivatives thereof from the correspondingly substituted 4-methyl-quinoline and 1-acyl(or 1-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters (or acetaldehyde) through alternative series of reaction steps which comprise, condensation, halogenation, deacylation, reduction, cyclization and hydroxylation, is described. Also described is the preparation of 1-acyl(or 1-H)-3vinyl-4-piperidineacetic acids and esters thereof and 1-acyl-3vinyl-4-piperidineacetaldehyde utilizing the corresponding 7acyldecahydro-2H-pyrido(3,4-d)azepin-2-one, prepared from 2-acyl1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end products are useful as antimalarial and antiarrhythmic agents.

United States Patent [1 1 Gutzwiller et al.

[451 1 Feb. 4, 1975 Bettingen, Switzerland; Uskokovic, Milan Radoje,Montclair, NJ.

[73] Assignee: Hoffman-La Roche Inc., Nutley,

[22] Filed: Aug. 1, 1973 [21] Appl. No.: 384,765

Related U.S. Application Data [60] Division of Ser. No. 212,774, Dec.27, 1971, Pat. No. 3.772.302, which is a continuation-in-part of Ser.No. 108,784, Jan. 7, 1971, abandoned, which is a continuation-in-part ofSer. No. 837,354, June 29,

1969, abandoned, which is a continuation-in-part of Ser. No, 741,914,July 2, 1968, abandoned.

[52] U.S. Cl...... 260/287 R, 260/284 R, 260/288 R, 260/289 R,260/293.88, 424/258 [51] Int. Cl C07d 43/24 [58] Field of Search260/287, 288

[56] References Cited UNITED STATES PATENTS 3,753,992 8/1973 Gutzwillerct al. 260/284 3,772,302 11/1973 Gutzweiller ct a1 260/284 OTHERPUBLICATIONS Chemical Catalogue for Pfaltz and Bauer, lnc. pg. 184, No.D 55240.

Primary Examiner-Donald G. Daus Assislanl Examiner-D. Wheeler Attorney,Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G. lsgro [57]ABSTRACT The preparation of quinine, quinidine, isomers and derivativesthereof from the correspondingly substituted 4-methyl-quinoline andl-acyl(or 1-H)-3-vinyl(or lower alkyl)-4-piperidine acetic acid esters(or acetaldehyde) through alternative series of reaction steps whichcomprise, condensation, halogenation, deacylation, reduction,cyclization and hydroxylation, is described. Also described is thepreparation of 1-acyl(or l-H)-3-vinyl-4-piperidineacetic acids andesters thereof and 1-acyl-3-vinyl-4-piperidineacetaldehyde utilizing thecorresponding 7-acyldecahydro-2H- pyrido[3,4-d]azepin-2-one, preparedfrom 2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone. The end productsare useful as antimalarial and antiarrhythmic agents.

5 Claims, N0 Drawings 1 a[3(R)-ALKYL-4(R) PIPER IDYL METHYL]-B-(6,7SUBSTITUTED-4 QUINOLYL)-2-ALKANOYLOXY PROPANE AND RACEMATESCROSS-REFERENCE TO RELATED APPLICATIONS This is a division, ofapplication Ser. No. 212.774 now Pat. No. 3,772,302 filed 12/27/71,which in turn is a c.i.p. of Ser. No. 104.784, filed l/7/7l, nowabandoned. which is a c.i.p. of Ser. No. 837,354, filed 6/27/69, nowabandoned. which is a c.i.p. of Ser. No. 741.914, filed 7/2/68. nowabandoned.

BRlEF SUMMARY OF THE INVENTION The invention relates to a process forpreparing quinine, quinidine, isomers and derivatives thereof whichcomprises:

a. condensing the correspondingly substituted 4- methylquinoline withracemic or optically active cis or trans l-acyl (or l-H )-3-vinyl(orlower alkyl)-4- piperidineacetic acid ester to yield the correspondingracemic or optically active cis or trans 4-{3-[ l-acyl(orl-H)-3-vinyl(or lower alkyl)-4-piperidyl]-2-oxopropyl}quinoline;

b. deacylating, if necessary, and reducing the product of step (a) toyield the corresponding racemic or optically active epimeric 4-{cis ortrans-3-[3-vinyl(or loweralkyl)-4-piperidyl]-2e-hydroxypropyl}quinolines. lf desired. thisreaction product can be acylated to yield racemic or optically activeepimeric 4-{cis or trans-3-l3- vinyl(or loweralkyl)-4-piperidyl]-2-eacyloxypropyl}quinolines or dehydrated to yieldracemic or optically active cis or trans 4-{cis or trans 3-[3- vinyl(orlower alkyl)-4-piperidyl] prop-lenyllquinolines;

c. an alternate process comprises condensing the correspondinglysubstituted 4-methylquinoline with racemic or optically active cis ortrans l-acyl-3-vinyl(or lower alkyl)-4-piperidineacetaldehyde to yieldthe corresponding racemic or optically active epimeric 4-{cis ortrans-3-[ l-acyl-3-vinyl(or lower alkyl)-4-piperidyl]-Ze-hydroxypropyllquinolines, and deacylating this reaction product toyield the corresponding racemic or optically active epimeric 4-{cis ortrans-3-[3-vinyl (or loweralkyl-4-piperidyl]-2e-hydroxypropyl}quinolines;

d. cyclizing the hydroxy, acyloxy or prop-l-enyl quinoline product ofstep (b) or (c) to the corresponding racemic or optically active4-{a-[5-vinyl(or lower alkyl)-2-quinuclidinyl]-methyl}quinoline,epimeric in positions 2 and er hydroxylating the product of step (d) toyield the corresponding racemic or optically active a-[5-vinyl(or loweralkyl)-2-quinuclidinyl]-4-quinolinemethanol, epimeric in positions a, 2and 5; and

f. recovering the desired reaction product.

An alternate process comprises:

g. halogenating the product of step (a) above to yield the correspondingracemic or optically active epimeric 4 {cis or trans 3-[l-acyl-3-vinyl(or lower alkyl)-4-piperidyll-le-halo-Z-oxopropyl}quinolines;

h. reducing the product of step ('g) with subsequent cyclization toyield a mixture of the corresponding racemic or optically activeepimeric 4-{cis or trans-3-[ lacyl-3-vinyl(or loweralkyl)-4-piperidyl]-le, 2eoxapropyl}quinolines;

i. deacylating the product of step (g) to yield a mixture of thecorresponding racemic or optically active epimeric 4- {cis or trans3-[3-vinyl(or lower alkyl-4- piperidyH-le, 2e-oxapropyl}quinolines;

j. cyclizing the product of step (h) to yield the-corre sponding racemicor optically active a-[5-vinyl(or loweralkyl)-2-quinuclidinyll-4-quinolinemethanol, epimeric in positions a, 2and 5; and

k. recovering the desired reaction product.

The end products are useful as antimalarial and antiarrhythmic agents.

In another aspect. the invention relates to a process for preparingracemic or optically active cis or trans lacyl(orl-H)-3-vinyl-4-piperidineacetic acid and esters thereof and racemic oroptically active cis or trans lacyl-3-vinyl-4-piperidineacetaldehyde by:

a. nitrosating a racemic or optically active cis or trans7-acyl-decahydro-2H-pyrido[3,4-d]azepin 2-one to yield the correspondingracemic or optically active cis or trans7-acyl-l-nitroso-decahydro-2H-pyrido[3,4- dlazepin-Z-one;

b. pyrrolyzing the reaction product of step (a) to yield thecorresponding racemic or optically active cis or transl-acy|-3-vinyl-4-piperidineacetic acid; and

c. hydrolyzing, if desired, and esterifying the reaction product of step(b) to yield the corresponding racemic or optically active cis or transl-acyl(or l-H )-3-vinyl-4- piperidineacetic acid ester; and

d. reducing and acylating the reaction product of step (c) to yieldracemic or optically active cis or translacyl-3-vinyl-4-piperidineacetaldehyde.

In a further aspect, the invention relates to an alternate process forpreparing racemic or optically active cis and trans l-acyl(orl-H)-3-vinyl-4-piperidineacetic acid and esters thereof by:

a. alcoholizing a racemic or optically active cis or trans7-acyl-decahydro-2H-pyrido[3,4-dlazepin-2-one to yield the correspondingracemic or optically active cis or transl-acyl-3-(2-aminoethyl)-4piperidineacetic acid esters;

b. methylating the reaction product of step (a) to yield thecorresponding racemic or optically active cis or -transl-acyl-3-(Z-dimethylaminoethyl)-4- piperidineacetic acid esters;

c. oxidizing the reaction product of step (b) to yield the correspondingracemic or optically active cis or transl-acyl-3-(2-dimethylaminoethyl)-4- piperidineacetic acid ester N-oxide;and

d. pyrolyzing the reaction product of step (c) to yield the desiredacetic acid and esters thereof.

ln still another aspect, the invention relates to a process forpreparing racemic or optically active cis or trans7-acyl-decahydro-2H-pyrido[3,4-d]azepin-2-one which comprises: a

a. hydrogenating a racemic or optically active2-acyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone to yield thecorresponding racemic or optically active cis or trans2-acyloctahydro-6(-ZH)-isoquinolone; and

b. converting the reaction product of step (a), through a SchmidtRearrangement, to the corresponding racemic or optically active cis ortrans 7-acyldecahydro-2H-pyrido[3,4-d]azepin-2-one.

Alternatively, by a process which comprises:

a. converting, though a Schmidt Rearrangement, a racemic or opticallyactive 2-acyl-l ,3,4,7,8,8a-hexahydro-6(2H )-isoquinolone to thecorresponding racemic or optically active2-acyl-l,2,3,4,7,8,9,9a-octahydro- 6H-pyrido[3,4-dlazepin-6-one; and

b. hydrogenating the reaction product of step (a) to yield thecorresponding racemic or optically active cis or trans7-acyldecahydro-2H-pyrido[3.4-dlazepin- 2-one.

In yet another aspect, the invention relates to novel compounds.

Detailed Description of the Invention The term lower alkyl" as usedherein denotes a hydrocarbon group containing l-7 carbon atoms. such asmethyl, ethyl. propyl. butyl and the like; methyl and ethyl arepreferred. The term "lower alkoxy" denotes a lower alkyl ether group inwhich the lower alkyl moie ty is described as above. such as methoxy.ethoxy. propoxy. butoxy and the like; methoxy and ethoxy are preferred.The term halogen" denotes all of the halogens. i.e.. bromine, chlorine,fluorine and iodine. Preferred are chlorine and bromine. The term acyl"denotes lower alkanoyl of 1-7 carbon atoms such as formyl. acetyl.propanoyl, butanoyl, heptanoyl. and the like; ar-lower alkanoyl.preferably phenyl-lower alkanoyl. wherein phenyl may be substituted byone or more lower alkyl. lower alkoxy or halogen groups such as benzoyland the like. The term aryl means phenyl which may be substituted by oneor more lower alkyl. lower alkoxy or halogen groups. The term aralkyl"means a hydrocarbon group of 7-12 carbon atoms such as benzyl.phenethyl, phenylpropyl and the like. The term acyloxy means an acyloxywherein the acyl moiety is as hereinbefore described, for example. loweralkanoyloxy and ar-lower alkanoyl'oxy.

The process for preparing quinine. quinidine. isomers and derivativesthereof is exemplified by Reaction Scheme la. la. la". lb. lb and lb.

Scheme Ia X IXa Vla VH3 wherein m is O, i or 2; R, is hydrogen, hydroxy,halogen, trifluoromethyl, lower alkyl, lower alkoxy, or when m is 2, Rtaken together with an adjacent R is also methylenedioxy; R is vinyl orlower alkyl, preferably ethyl; R is hydrogen or lower alkyl; R ishydrogen or acyl; and R,-, is lower alkyl, aryl or ar-lower alkyl. As isevident from the above when m is 2, R, or the like is individuallyselected from the various groupings hereinbefore described. Compounds ofthe formula la and lla above are useful as antimalarial andantiarrhythmic agents.

in Reaction Scheme la, 4-methyl-quinolines of formula X, which are knowncompounds or are analogs of known compounds readily obtained by knownprocedures, are condensed with l-acyl (or l-H)-3(R)- vinyl(or loweralkyl)-4(S)-piperidineacetic acid ester of formula lXa, antipode or itsracemate which are known compounds, are analogs of known compoundsreadily obtained by known procedures, or are prepared as hereinafterdescribed, in the presence of a base, for

example, sodium hydride, an alkali metal alkoxide such as sodiummethoxide, or lithium dialkyiamide such as lithium diisopropylamide toyield 4-{3-[ i-acyl(or 1-H)- 3(R)-vinyl(or loweraikyl)-4(S)-piperidyl1-2- oxopropyl}quinoline of formula Villa, antipodeor its racemate. The condensation is suitably carried out at roomtemperature; however, temperatures above or below room temperature maybe employed. Preferably, the condensation is conducted at a temperaturewithin the range of about 70 and about 50C. Moreover, the condensationcan be suitably carried out in the presence of an inert organic solvent,for example, a hydrocarbon, such as benzene, hexane and the like, or anether such as ether, tetrahydrofuran or dioxane, or dimethylformamide orhexamethylphosphoramide.

The 4-{3-[1 -acyi(or 1-H)-3(R)-vinyl(or lower alkyl)- 'P P?FiYll'ZtQZQPIQPXU i1in9iit of formula Villa, antipode or its racemate isconverted to th'fiii'i ture of epimeric 4-{3-[3(R)-vinyl(or loweralkyl)-4(S)- piperidyl]-2e-hydroxypropyl quinolines of formula Via,their antipodes or racemates by simultaneous deacylation, if necessary,and reaction. The deacylation and reduction are conveniently effectedutilizing a reducing agent, for example, diisobutylaluminum hydride,sodium aluminum hydride and the like, in an inert organic solvent, forexample, a hydrocarbon such as benzene or toluene, ether,tetrahydrofuran and the like. The deacylation and reduction are suitablycarried out at room temperature or below, preferably, at a temperaturewithin the range of about 70 to about 25C. The reduction and deacylationcan also be carried out stepwise, i.e.. by first reducing a compound offormula Villa, wherein R is acyl. with sodium borohydride, followed bydeacylation utilizing. for example. aqueous hydrochloric or sulfuricacid as the deacylating agent. if desired, the compound of formula Viacan be esterifled to the corresponding mixture of epimeric 4-{3-[3(R)-vinyl(or lower alkyl)-4(S)-piperidyll-Ze-acyloxypropyl}quinolinesof formula Vila, their antipodes or racemates utilizing knownprocedures, for example. reaction with the corresponding organic acid inthe presence of a catalyst, such as boron trifluoride. Alternatively, ifdesired. the compound of formula Via can be converted to cis and trans4-{3-[3(R)-vinyl(or lower alkyl)-4(R) -piperidyl]-prop-lenyl}quinolinesof formula Va, their antipodes or racemates utilizing a dehydratingagent such as thionyl chloride, phosphorus oxychloride, phosphoruspentachloride and the like, in the presence of an organic base, forexample, a tertiary amine such as pyridine, triethylamine and the like,at a temperature within the range of about to about room temperature.

The cyciization of epimeric 4- {3-[3(R)-vinyl(or loweralkyl)-4(S)-piperidyl]-2e-hydroxy(or acyloxy)- propyl}quinolines offormulas Via and Vila, their antipodes or racemates, respectively, andcis and trans 4- {3-[3(R)-vinyl(or lower alkyl)-4(R)-piperidyi] prop-ienyl}quinolines of formula Va, their antipodes or racemates to 4-{a-[(R)-vinyl(or lower alkyl)-4(S)- quinuclidin-2(S) and 2(R)-yl]-methyl}quinolines of formulas ilia and Wu, their antipodes or its racemate iscarried out utilizing a cyclizing agent, for example, an organic acid,such as glacial acetic acid or the like. The cyciization is suitablycarried out at room temperature; however, temperatures above or belowroom temperature may also be employed. it is prefereed to employ atemperature within the range of about to about 100C. Moreover, thecyciization can be conveniently conducted in the presence of an inertorganic solvent, for example, a hydrocarbon such as benzene or toluene,or an ether, such as diethyl ether or tetrahydrofuran.

The hydroxylation of the compounds of formulas llia and lVa or theirracemates to a(R)-[5(R)-vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl]-4- quinolinemethanol of formula la, itsantipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula iia, its antipode orracemate, respectively, is carried out, for example, in the presence ofmolecular oxygen and a reducing agent, such as dimethylsulfoxide,pyridine, triphenylphosphine, platinum black, or a trialkylphosphite,such as triethylphosphite, or the like, in a strongly basic solution.

A suitable base for the reaction described above comprises, for example,an alkali metal alkoxide, such as potassium t-butoxide, sodiumt-butoxide, sodium isoamylate, sodium methoxide or the like, or analkali metal amide, such as lithium diisopropylamide, sodium amide orthe like. Conveniently, a solvent such as dimethylsulfoxide,dimethylformamide, hexamethylphosphoramide, pyridine, t-butanol, ahydrocarbon such as benzene or toluene, an ether such astetrahydrofuran, dioxane or the like, or mixtures thereof can beutilized. A preferred reaction medium comprises a mixture ofdimethylsulfoxide and t-butanol in the presence of potassium t-butoxide.

(1mm J \N/ Ila wherein R., R R, and m are as previously described and Xis halogen. X

In Reaction Scheme la", an alternative process for the conversion ofcompounds of formula Vllla to the compounds of formulas la and lla isdescribed. The conversion ofthe 4- {3-[ l-acyl-3( R)-vinyl(or loweralkyl)-4(S)-piperidyl]-2-oxopropyl }quinoline of formula Vllla, itsantipode or racemate to the corresponding mixture of epimeric 4- {3-[l-acyl-3(R)-vinyl(or lower alkyl )-4(S )-piperidyl le-halo-Z-oxopropyl}quinolines of formula XXa, their antipodes orracemates, respec tively, is effected utilizing a halogenating agentsuch as N-bromo-succinimide, N-chloro-succinimide, N- bromoacetamide andthe like. The halogenation can be conducted in an inert organic solvent,for example, a hydrocarbon such as benzene, toluene and the like, ahalogenated hydrocarbon such as carbon tetrachloride; an ether such asdiethylether, tetrahydrofuran, dioxane and the like. Conveniently, thereaction can be initiated by a free radical catalyst such asdibenzoylperoxide or by irradiation with infrared. The temperature isnot critical. however. it is preferred to conduct the reaction at atemperature in the range of about room temperature and the refluxtemperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXa. their antipodesor racemates to the corresponding mixture of diastereomeric 4-{3-ll-acyl-3l R vinyl(or lower alkyl)-4(S)-piperidyl]-le,Zeoxapropyl}quinolines of the formula XXla. their antipodes or racematescan be effected utilizing a reducing agent. for example, alkali metalhydrides such as sodium borohydride, potassium borohydride, lithiumtritertiarybutoxyaluminum hydride and the like. The reduction isconveniently effected in an inert organic solvent. for example,aliphatic alcohols such as methanol, ethanol and the like; ethers suchas diethylether, tetrahydrofuran, dioxane and the like, at a temperaturein the range of about -7()C. and about the reflux temperature of thereaction mixture.

The conversion of the compound of formula XXla to the correspondingmixture of the diastereomeric 4- {3- [3(R)-vinyl(or loweralkyl)-4(S).-piperidyl]-le, 2eoxopropyl}quinolines of the formula XXlla,their antipodes or racemates is effected using a deacylating agent, forexample, alkali hydroxides such as sodium hydroxide. potassiumhydroxide, or a reducing deacylating agent, for example, dialkylaluminumhydride such as diisobutylaluminum hydride, or an alkali metal aluminumhydride such as lithium aluminum hydride, sodium aluminum hydride andthe like. The deacylation is conveniently conducted in the presence ofan inert organic solvent, for example, lower alkanols such as methanol,ethanol and the like, hydrocarbons such as toluene and the like, etherssuch as diethylether, tetrahydrofuran and the like. The deacylationtemperature is not critical. Conveniently, it may be in the range ofabout C. to about the reflux temperature of the reaction mixture.

The conversion of the compounds of formula XXlla to the correspondingmixture comprising a(R)-[5- quinolinemethanol loweralkyl)-4(S)-quinuclidin-2(S)- yl]-4-quinolinemethanol of formula la, itsantipode or racemate and a(S)-[5(R)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yll-4-quinolinemethanol of formula lla, its antipode orracemate is effected by reaction with a weak organic or inorganicprotonic acid, for example, water, ammonium chloride, lower alkanolssuch as methanol, ethanol and the like, Lewis acids such as aluminumoxide, aluminum chloride, boron trifluoride and the like. Conveniently,conversion is conducted in the presence of an inert organic solvent, forexample, carbon disulflde, hydrocarbons such as benzene, toluene and thelike, chlorinated hydrocarbons such as dichloromethane,carbontetrachloride, chloroform and the like, and ethers such asdiethylether, tetrahydrofuran, dioxane and the like. The temperature ofthe reaction is not critical. Conveniently, it may be in the range ofabout 0C. and about the reflux temperature of the reaction mixture.

( om (B1) 1111) lV b wherein R,, R R R R and m are previously described.

The hereinafter described reaction steps of Reaction Scheme lb areeffected utilizing the procedures and conditions set forth in Scheme la.The 4-methylquinoline of formula X is condensed with l-acyl(or l-H)-3(S)-vinyl(or lower alkyl)-4(S)-piperidineacetic acid ester offormula lXb, its antipode or racemate to yield 4-{3-[ l-acyl(orl-H)-3(S)-vinyl(or lower alkyl)- 4(S)-piperidyl]-2-oxopropyl quinolineof formula Vlllb, its antipode or racemate. The compound of formulaVlllb is deacylated, if necessary, and reduced to and2(R)-yl]-methyl}quinolines of formulas lllb and Nb, their antipodes orracemates. The compounds of formulas lllb and Nb are hydroxylated toa(R)-[5(S)- vinyl(or lower alkyl)-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol of formula lb, its antipode or race- 5 .mate and 01(5)-[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula llc, its antipode orracemate, respectively.

The hydroxylation of the compound of Formulas llla,b-lVa,b to the endproducts of Formulas la,b-lla,b,

IIIa, b-IVa, b

can also be effected utilizing molecular oxygen and a catalyst such asplatinum, tris(triphenylphosphine)rhodium chloride or the like or byoxidation utilizing a compound such as selenium dioxide, rutheniumtetroxide, palladium acetate, mercuric acetate, thallium triacetate,manganese dioxide, cerium (lV) oxide, or the like.

( 1)", N Vlllb' R"\;'I/\N n u 9 f1 (Rom w N .\.\llh

IR: Rg I-' II N II (R1)m (Rim) I N Ib N b wherein R R R,, m and X are aspreviously described. ln Reaction Scheme lb", an alternative process forthe conversion of compounds of formula Vlllb to the compounds offormulas lb and [lb is described. The

conversion of the 4-{3-[ l-acyl-3(S)-vinyl(or loweralkyl)-4(S)-piperidy|]-2-oxopropyl quinoline of formula Vlllb', itsantipode or racemate to the corresponding mixture of epimeric 4- {3-[l-acyl-3(S)-vinyl(or lower alkyl )-4(S )-piperidyl]-le-halo-2-oxopropyl}quinolines of formula XXb, their antipodes orracemates, respectively, is effected utilizing a halogenating agent suchas N-bromo-succinimide, N-chloro-succinimide, N- bromoacetamide and thelike. The halogenation can be conducted in an inert organic solvent, forexample, a hydrocarbon such as benzene, toluene and the like. ahalogenated hydrocarbon such as carbon tetrachloride; an ether such asdiethylether, tetrahydrofuran, dioxane and the like. Conveniently, thereaction can be initiated by a free radical catalyst such asdibenzoylperoxide or by irradiation with infrared. The temperature isnot critical, however, it is preferred to conduct the reaction at atemperature in the range of about room temperature and the refluxtemperature of the reaction mixture.

The conversion of the epimeric compounds of formula XXb, their antipodesor racemates to the corresponding mixture of diastereomeric 4- {3-[l-acyl-3(S)- vinyl(or lower alkyl)-4(S)-piperidyl]-le,2eoxaprepyl}quinolines of the formula XXlb. their antipodes or racematescan be effected utilizing a reducing agent, for example, alkali metalhydrides such as sodium borohydride, potassium borohydridc, lithium tritertiarybutoxyaluminum hydride and the like. The reduction isconveniently effected in an inert organic solvent, for example,aliphatic alcohols such as methanol, ethanol and the like; ethers suchas diethylether, tetrahydrofuran, dioxane and the like, at a temperaturein the range of about -7()C. and about the reflux temperature of thereaction mixture.

The conversion of the compound of formula XXlb to the correspondingmixture of the diastereomeric 4-{3- [3(S)-vinyl(or loweralkyl)-4(S)-piperidyl]-l6,26-

oxapropyl} quinolines of the formula XXIlb. their antipodes or racematesis effected using a deacylating agent, for example, alkali hydroxidessuch as sodium hydroxide, potassium hydroxide, or a reducing deacylatingagent, for example, dialkylaluminum hydride such as diisobutylaluminumhydride, or an alkali metal aluminum hydride such as lithium aluminumhydride, sodium aluminum hydride and the like. The deacylation isconveniently conducted to the presence of an inert organic solvent, forexample, lower alkanols such as methanol, ethanol and the like,hydrocarbons such as toluene and the like, ethers such as diethylether,tetraliydrol'uran and the like. The deaeylation temperature is notcritical. Conveniently, it may be in the range of about 70C. to aboutthe reflux temperature of the reaction mixture.

The conversion of the compounds of formula XXIIb to the correspondingmixture comprising t(R)-[5'(S)- vinyl(or loweralkyl)-4(S)-quinuclidin-2(S)-yl1-4- quinolinemethanol of formula Ib, itsantipode or racemate and 0z(S)-[5(S)-vinyl(or lower alkyl)-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol of formula llb, its antipode orracemate is effected by reaction with a weak organic or inorganicprotonic acid, for example, water, ammonium chloride, lower alkanolssuch as methanol, ethanol and the like, Lewis acids such as aluminumoxide, aluminum chloride, boron trifluoride and the like. Conveniently,conversion is conducted in the presence of an inert organic solvent, forexample, carbon disulfide, hydrocarbons such as benzene, toluene and thelike, chlorinated hydrocarbons such as dichloromethane,carbontetrachloride, chloroform and the like, and ethers such asdiethylether, tetrahydrofuran, dioxane and the like. The temperature ofthe reaction is not critical. Conveniently, it may be in the range ofabout 0C. and about the reflux temperature of the reaction mixture.

The various other process aspects of the invention are exemplified bythe following reaction schemes Ila, llb, Illa, lllb and IV.

XIIIa wherein R and R are as previously described. and

R, is lower alkyl, aryl or ar-lower alkyl.

In Reaction Scheme Ila, the conversion of 7-acyldecahydro-ZH-pyridol 3(R ),4(S )-d lazepin-Z-one of formula XIa, its antipode or racemate to7-acyl-lnitrose-decahydro-ZH-pyrido[ 3( R),4( S )-d ]-azepin- 2-one offormula Xlla, its antipode or racemate, respectively, is carried oututilizing a'nitroseting agent, such as, for example, sodium nitrite ordinitrogen tetroxide. Conveniently, the reaction can be conducted in thepresence of a solvent, for example, an organic acid such acetic acid, ora chlorinated hydrocarbon such as carbon tetrachloride. The nitrosationis conveniently conducted at a temperature within the range of about 0C.to about room temperature. preferably at 0C.

The compound of formula XIIa is converted toacyl-3tR)-vinyl-4(S)-piperidineacetic acid of formula Xllla, itsantipode or racemate, respectively, by pyrolysis. Conveniently, thepyrolysis is conducted at a temperature within the range of about roomtemperature to about 200C, preferably at a temperature within the rangeof about C. to about C. Conveniently, a high boiling solvent such asxylene, decaline and the like, can be utilized in the reaction.

The compound of formula Xllla is converted to alacyl(orI-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula IXc, itsantipode or racemate, respectively, utilizing an esterifying agent, forexample, a lower alkanol, such as methal, ethanol, propanol and thelike, in the presence of, for example, an inorganic acid such ashydrochloric acid, sulfuric acid and the like. When R is hydrogen,however, the esterification is preceded by hydrolysis in the presenceof, for example, an aqueous inorganic acid, such as hydrochloric acid,sulfuric acid and the like.

Compounds of formula Xla, wherein R is alkyl, for instance, ethyl, canbe prepared as described in Scheme IV.

Scheme IIb XIIIb O Ra wherein R R, and R are as previously described.

In alike manner, in Reaction Scheme IIb, the conversion of7-acyl-decahydro-2H-pyrido[3(S),4(S)- dlazepin-Z-one of Formula Xlb, itsantipode or racemate to 7-acyl- I -nitroso-decahydro-2H-pyrido[3(S),4(S)-d]azepin-2-one of Formula XIIb, its antipode orracemate, respectively, is carried out. The compound of Formula XIIb isconverted to l-acyl- 3( S )-vinyl-4( S )-piperidineacetic acid ofFormula Xlllb, its antipode or racemate. respectively, by pyrolysis. Thecompound of Formula Xlllb is converted to lacyl(orl-H)-3(S)-piperidineacetic acid ester of Formula lXd. its antipode orracemate. respectively.

SFIIEME Illa wherein R R and R are as previously described.

ln Reaction Scheme llla, 7-acyl-decahydro-2H-pyrido[3(R).4(S)-d]azepin-2-one of formula Xla, its antipode or racemateis converted to l-acyl-3(R)-(2- aminoethyl)-4(S)-piperidineacetic acidester of formula XlVa, its antipode or racemate. respectively. utilizingan alcoholizing agent, for example, a lower alkanol such as methanol.ethanol. propanol and the like. in the presence of. for example.anhydrous inorganic acid such as hydrochloric acid. sulfuric acid andthe like. Conveniently. the alcoholysis is conducted at a temperaturewithin the range of about room temperature to about the boiling point ofthe alkanol.

The compound of formula XlVa is converted tolacyl-3(R)-(2-dimethylaminoethyl)--l(S)- piperidineacetic acid ester offormula X'Va. its antipode or racemate. respectively. utilizing amethylating agent such as. for example. formic acid/formaltlehydemixture or formaldehyde/Raney nickel. The N- methylation is convenientlyconducted at a temperature within the range of about room temperature toabout the boiling point of the methylating agent.

The compound of formulaXVa is converted tolacyl-3(R)-(2-dimethylaminoethyl)-4(S)- piperidineacetic acid esterN-oxide (if formula XVla. its antipode or racemate. respectively,utilizing an oxidizing agent. for example. hydrogen peroxide or aperorganic acid such as, peracetic acid. The oxidation is convenientlyconducted in the presence of a solvent, for example. lower alkanol, suchas methanol, ethanol. propanol and the like. or a hydrocarbon such asbenzene and the like. The oxidation is conveniently conducted at atemperature within the range of about 0 to about room temperature.preferably at 0C.

The compound of formula XVla is converted to lacyl(orl-H)-3(R)-vinyl-4(S)-piperidineacetic acid ester of formula lXc, itsantipode or racemate. respectively, by pyrolysis. Such pyrolysis isconveniently conducted at a temperature in the range of about to about200C, preferably at a temperature within the range of about to about C.When R is hydrogen. however, the pyrolysis is followed by hydrolysis andreesterification.

SCHEME IlIb COOR;

Ru XlVb COOR:

N (CHa):

podc or racemate, respectively. The compound of Formula XVb is convertedto l-acyl-3(S)-(2- dimethylaminoethyl)-4(S)-piperidineacetic acid esterN-oxide of Formula XVlb, its antipode or racemate, respectively. Thecompound of Formula XVlb is converted to l-acyl(r l-H-3(S)-vinyl-4(S)-piperidineacetic acid ester of Formula lXd, its antipode or racemate.

SCHEME 1V O OII ILA,

I N N A I o R, o n.

xvn XIX XIb wherein R is as previously'described.

In the Reaction Scheme lV, racemic Z-acyll,3,4,7,8.8a-hexahydro-6(2H)-isoquinolene of formula XVIl is converted to the racemic cis andtrans Z-acyloctahydro-6(2H )-isoquinolones of formula XVllla and XVlllb,respectively, utilizing a hydrogenating agent, for example. hydrogen inthe presence of palladium or rhodium catalyst. Conveniently. thehydrogenation can be conducted in the presence ofa solvent. for example,a lower alkanol such as methanol, ethanol, propanol and the like, withor without an inorganic acid such as hydrohalic acid, for example,hydrochloric acid and the like. The hydrogenation can be convenientlyconducted at a temperature within the range of about roo temperature andabout 50C.

The racemates of the compounds of formula XVllla or XVlllb are resolvedto the corresponding optical antipodes by conventional methods which arefurther illustrated by Examples 3, 4, 5.

The conversion of 2-acyl-4a(S),8a(R)-octahydro- 6(2H)-isoquinolone offormula XVllla, its antipode or racemate to7-acyldecahydro-2H-pyrido[3(R),4(S)- d]azepin-2-one of formula Xla, itsantipode or racemate, respectively, is carried out utilizing the knownSchmidt rearrangement, i.e., the reaction of the compound of formulaXVllla with sodium azide in the presence of an inorganic acid such assulfuric acid or polyphosphoric acid, with or without solvent, at atemperature within the range of from about 0 to about C.

In a like manner, 2-acyl-4a(S),8a(S)-octahydro- 6(2H )-isoquinolone ofFormula XVlllb, its antipode or racemate is converted to7-acyl-decahydro-2H- pyridol3(S),4(S)-dlazepin-2-one of Formula Xlb, itsantipode or racemate, respectively.

The racemic compound of Formula XVII is converted to the racemic2-acyl-l ,2,3,4,7,8,9,9aoctahydro-6H-pyrido[3,4-d]azepin-6-one ofFormula XIX utilizing the Schmidt rearrangement as hereinbeforedescribed. The compound of formula XlX is converted to the racemiccompound of Formula Xla utilizing a hydrogenating agent such as hydrogenin the presence of a catalyst, such as rhodium or palladium, in asolvent, for example, an alkanol, such as ethanol, methanol and thelike, in the presence of an inorganic acid, such as hydrochloric acid.

In another aspect, the invention relates to the compounds of formulaslb, llb, lllb, lVb, Va, Vb, Vla, Vlb, Vlla, Vllb, Villa, Vlllb, lXb,Xla, Xlb, Xlla, Xllb, Xlllb, XlVa, XlVb, XVa, XVb, XVla, XVlb and XlX.

The compounds of formulas lb and llb are useful as antimalarial andantiarrhythmic agents; all the other compounds listed in the aboveparagraph are useful intermediates.

In still another aspect, the invention relates to compounds of theformulas ule and (Ruln IIIc IVo when R is other than hydrogen and n is1, R is lower alkoxy, lower alkyl, hydroxy, hydrogen, trifluoromethyl,halogen, or taken together with an adjacent R is methylenedioxy; andwhen R is other than hydrogen and n is 2, R is hydrogen, and theirantipodes and racemates.

Also included in the purview of the invention are compounds of theformulas wherein R is methyl or C C lower alkyl. their antipodes andracematcs. Compounds of formulas lllc, llld, We and lVd are usefulintermediates.

in still another aspect, the invention relates to compounds of theformulas 1 u bi H ClhO- and IVe

wherein n is O to 2; R- is vinyl or lower alkyl; R is hydrogen, hydroxy,lower alkyl, lower alkoxy, trifluoromethyl. halogen. or when n is 2, Rtaken together with an adjacent R is also methylenedioxy; when R ishydrogen, R is C -C alkoxy. lower alkyl, trifluoromethyl or halogen;when R is other than hydrogen and n is l, R; is lower alkoxy, loweralkyl. hydrogen. trifluoromethyl. halogen, or taken together with anadjacent R is methy'lenedioxy; and when R is other than hydrogen and nis 2, R is hydrogen and their antipodes and racemates.

As is evident from the above R, or R or the like are individuallyselected from the various groupings hereinbefore described. Morover,when m or n is 2, R or R or the like can additionally form with anadjacent R or R or the like the methylenedioxy radical. Thus. eitherwhen morn is l or 2, R or R or the like can individually also representhydrogen, hydroxy, halogen, lower alkyl, lower alkoxy ortrifluoromethyl. Additionally, when m or n is 2, two adjacent groupingsof R or R can together represent methylenedioxy.

ln yet another aspect, the invention relates to compounds of theformulas wherein R is methyl or C -C lower alkyl, their antipodes andracemates.

relates to comwherein n is 0 to 2; R is vinyl or lower alkyl; R ishydrogen, hydroxy, lower alky, lower alkoxy, trifluoromethyl or halogen,and when n is 2, R taken together with an adjacent R is alsomethylenedioxy; when R is hydrogen, R is C -C alkoxy. lower alkyl,trifluoromethyl or halogen; when R is other than hydrogen and n is 1, Ris lower alkoxy. lower alkyl, hydrogen, trifluoromethyl or halogen, ortaken together with an adjacent R is methylenedioxy; and when R is otherthan hydrogen and n is 2, R is hydrogen, and their antipodes andracemates.

and pharmaceutically acceptable acid addition salts.

Exemplary of the compounds of formulas lc and lie are:

6,8-dimethoxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yl[-4-quinolinemethanol [hereinafter referred to as6.8'-dimethoxy-3-epi-dihydrocinchonidinelits antipode and racemicanalog;

7 -chloro-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as 7-chloro-3-epi-dihydrocinchonidine[its antipode and racemic analog; 4

6,7-methylenedioxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as6,7-methylenedioxy-3-epi-dihydrocinchonidine1its antipode and racemicanalog;

7-trifluoromethyl-a( R 5( S )-ethyl-4(S)-quinuclidin-2(S)-yll-4-quinolinemethanol [hereinafter referred to as7-trifluoromethyl-3antipode its antipode and racemic analog;

6,8-dimethoxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yll-4-quinolinemethanol [hereinafter referred to as6,8-dimethoxy-3-epi-dihydrocinchonine]its antipode and racemic analog;

7-chloro-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)- yll-4-quinolinemethanol[hereinafter referred to as 7'- chloro-3-epi-dihydrocinchonine]itsantipode and racemic analog;

6,7-methylenedioxy-a(S)-[5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as6,7-methylenedioxy-3-epi-dihydrocinchonine]its antipode and racemicanalog;

7-trifluoromethyl-a(S)-[5(S)-ethy1-4(S)-quinuclidin-2(R)'yl[-4-quinolinemethanol [hereinafter referred to as7'-trifluoromethyl-3-epi-dihydrocinchonine]its antipode and racemicanalog.

Also included in the purview of the invention are compounds of theformulas CH; O CH;O

wherein R is vinyl, methyl or C -C alkyl. their antipodes and racematesand pharmaceutically acceptable acid addition salts.

Also included in the purview of the invention are compounds of theformula:

the antipode of 6-methoxy-a(R)-[5(S)-ethyl-4(S)-quinuclidin-2(S)-ylI-4-quinolinemethanol [hereinafter referred to as6'-methoxy-3-epi-dihydrocinchonidine or 3-epi-dihydroquinine] and itsracemic analog (Compound A) and the antipode of6-methoxy-a(S)-l5(S)-ethyl-4(S)-quinuclidin-2(R)-yl]-4-quinolinemethanol [hereinafter referred to as6-methoxy-S-epi-dihydrocinchonine or 3-epi-dihydroquinidine] and itsracemic analog (Compound B).

The compounds of formulas lc. Id, He and lld, as well I as Compounds Aand B, are useful also as antimalarial and antiarrhythmic agents.

The compounds of the formula lXa have demonstrated cardiovascularactivity, such as. hypotensive activity. The pharmacologically usefulcardiovascular activity is demonstrated in warm-blooded animalsutilizing standard procedures. For example. the test compound isadministered to anesthetized (30 mg/kg sodium pentobarbital).artificially respired (Palmer Pump) dogs. Femoral arterial bloodpressure and respiratory resistance (measured in terms of pressure) arerecorded on a direct writing oscillographic recorder. A series ofcontrolresponses of the blood pressure and respiration are obtained andduplicated. The control procedures used are: intravenously administerednorepinephrine (1 y/kg), histamine (l y/kg), serotonin (25 y/kg) andhypertensin (0.5 -y/kg) as well as the bilaterial occlusion of thecarotid arteries and the electrical stimulation of the central portionof a severed vagus nerve (SV, 50 c.p.s., 10 sec.). Each ofthe controlprocedures is administered at 5-minute intervals. Five minutes after theseries of control responses, the drug to be tested is intravenouslyadministered and its effects recorded. The series of control proceduresis repeated after dosing to determine the effect of the compound onthese standard responses. If the control responses are unaltered by thetest drug, a second compound is administered and the procedure repeated.If the test compound alters the blood pressure or the control responses,the control procedures are repeated at convenient intervals until theanimal has returned to its predose status or a new physiological statusis established.

When meroquinene-t-butylester D-monotartrate of d-inonotartrute isutilized as the test substance at a dose of4 mg/kg. intravenously, thefollowing results are obtained:

blood pressure -25 for 35 minutes serotonin N.E.

Central Vagus Stimulation slight inhibition Carotid Occlusion blockingHypertension N.E. Norcpincphrinc slight inhibition Histamine slightinhibition The compounds of Formula lXa also exhibit antiestrogenicactivity. This useful estrogenic activity is demonstrated inwarm-blooded animals. For example. the test compound is administeredonce daily for three consecutive days to groups of i0 immature femalerats (40-50 grams). On the first treatment day, all rats are injectedsubcutaneously with 025 mcg. estradiol in sesame oil. On the fourth day,uteri are removed at autopsy and weighed on a torsion balance.

When meroquinene-t-butylester d-monotartrate is utilized as the testsubstance at a dosage of 1 mg/kg. po, an 1 1 percent antiestrogeninhibition is observed with a l 2 percent uterine change.

The compounds of formulas la. lla, lb and llb. including compounds ofthe formulas lc. ld. He and lld. as well as compounds A and B. and theirpharmaceutically acceptable acid addition salts possess antimalarial andantiarrhythmic properties and are therefore useful as antimalarial andanti-arrhythmic agents. Their pharmacologically useful anti-arrhythmicactivity is demonstrated in warm-blooded animals utilizing standardprocedures, for example, the test compound is administered to preparedmongrel dogs. The chest cavity ofthe experimental animal previouslyanesthetized using a combination of sodium barbitol. 300 mg/kg. andpentobarbitol, l5 mg/kg., is opened up through the third rightinterspace under artificial respiration and the per icardium is cut andsutured to the wall of the thorax so as to maintain the heart inapericardial cradle throughout the course of the test procedure.Arterial pressure ins monitored by inserting a polyethylene cannula intothe aorta via the left carotid artery and is measured with anappropriate Statham pressure transducer. During the course of theexperiment, electrical activity of the heart is viewed both on anoscilloscope and recorded on a Sanborn polyviso using standard ECG leadII. The heart is also observed visually. The antiarrhythmic assay of thetest drug is undertaken using a modification of the method of Scherf andChick, A dripping of 1 percent solution of acetylcholine is applied tothe sinus node and the atrium is irritated by pinching with a pair offorceps. This procedure produces a continuous artiral arrhythmia whichmostly consists of atrial fibrillation. Since hypokalemiz produces asusceptibility to atrial fibrillation (Leveque,

7 1964), 2 units/kg, of insulin is administered 30 minutes before thestart of the acetylcholine drip. Once atrial fibrillation isestablished, there is a ten-minute waiting period before the test drugis administered. The test drugs are administered at the rate of lmg/kg/minute until normal sinus rhythm appears or until 30 mg/kg, ofdrug is administered.

When 6-methoxy-a(R)-[5(R)-ethyl-4(S)-quinuclidin-2(S)-yl]-4-quinolinemethanol is utilized as the test substance at a dosage of about 4.0mg/kg, an antifibrillatory effect is observed for more than 60 minutes.

Their pharmacological useful antimalarial activity is demonstrated inwarm-blooded animals using standard procedures, for example, the testsubstance is administered to albino mice in variable amounts. Albinomice are inoculated with about 5-l0 million red cells infected with P.Bergei. Treatment is started on the first day after inoculation, and thedrug is administered per during 4 consecutive days. On the seventh dayof infection, smears are made, stained with giemsa and microscopicallyexamined for P. Bergei.

When racemic 7'-metyhoxy-dihydrocinchonidine dihydrochloride or racemic7-methoxydihydrocinchonine dihydrochloride is utilized as the testsubstance at dosages in the range of 125 mg/kg. to about 250 mg/kg., themicroscopical examination of the blood smears is free of P. Bergei(negative). When 6-methoxyatRH504R)-l5(R)' y (S)-quinuclidin-2(S)-yll-4-quinolinemethanol [dihydroquinine] or6-methoxy-a(R)-[5(R)-ethyl-4(S)- quinuclidin-2(S)-yl-4-quinolinemethanolis utilized as the test substance at a dose of about 200 mg/kg, themicroscopical examination of the blood smears is free of P. Berghei(negative). The compounds of formulas la, Ila, lb and llb, including thecompounds of formulas lc, ld, llc and lid, as well as compounds A and B,and their pharmaceutically acceptable acid addition salts have effectsqualitatively similar, for example, to those of quinine and quinidine,known for their therapeutic uses and properties. Thus, the compounds ofthe invention demonstrate a pattern of activity associated withantimalarials and antiarrhythmics of known efficacy and safety.

Furthermore, the compounds of the formulas la, lla, lb and llb,including the compounds of formulas lc, ld, llc and lld, as well ascompounds A and B, can be utilized as flavoring agents in beverages inthe same manner as quinine is now used for this purpose.

The compounds of formulas la, lla, lb and llb, including the compoundsofformulas [0, Id, llc and 11d, as well as compounds A and fi,r0r5"amaitd'ffiafian and such salts are also within the scope of thisinvention. Thus, the compounds of formulas la, Ila, lb and llb,including the compounds of formulas lc, ld, llc and lid, as well ascompounds A and B, form pharmaceutically acceptable addition salts with,for example, both pharmaceutically acceptable addition salts with, forexample, both pharmaceutically acceptable organic and inorganic acids,such as acetic acid, succinic acid, formic acid, methanesulfonic acid,p-toluenesulfonic acid, hydrochloric acid, nitric acid, phosphoric acid,sulfuric acid, and the like.

The products of the invention can be incorporated into standardpharmaceutical dosage forms, for example, they are useful for oral orparenteral application with the usual pharmaceutical adjuvant materials,e.g., organic or inorganic inert carrier materials such as water,gelatin, lactose, starch, magnesium stearate, tale, vegetable oils,gums, polyalkyleneglycols, and the like. The pharmaceutical preparationcan be employed in a solid form, e.g., as tablets, troches,suppositories capsules, or in liquid form, e.g., as solutions,suspensions or emulsions. The pharmaceutical adjuvant material caninclude preservatives, stabilizers, wetting or emulsifying agents, saltsto change the osmotic pressure or to act as buffers. They can alsocontain other thereapeutically active materials.

The quantity of active medicament which is present in any of theabove-described dosage forms is variable. The frequency with which anysuch dosage form will be administered will vary. depending upon thequantity of active medicament present therein, and the needs andrequirements of the pharmacological situation.

Due to the possible different spatial arrangements of their atoms, it isto be understood that the compounds of this invention may be obtained inmore than one possible stereoisemeric form. The novel compounds. asdescribed and claimed. are intended to embrace all such isomeric forms.Accordingly, the examples included herein are to be understood asillustrative of particular mixtures of isomers or single isomers and notas limitations upon the scope of the invention. All temperatures are indegrees Centigrade. unless otherwise mentioned.

EXAMPLE I Preparation of racemic cis l-benzoyl-octahydro- 6(2Hisoquinolone from racemic 2-benzoyll,3,4,7,8.8a-hexahydro-6( 2H)-isoquinolone To a solution containing 151 g. of racemicZ-benzoyll,3,4,7,8,8a-hexahydro-6(2H)-isoquinolone in 3000 ml. ofabsolute ethanol were added 300 ml. of 3 N aqueous hydrochloric acid and30 g. of 5% rhodium on alumina catalyst. The mixture was hydrogenated atroom temperature and atmospheric pressure until the uptake of hydrogenceased. The catalyst was removed by filtration and washed thoroughlywith ethanol. The filtrate was partially evaporated in vacuo, dilutedwith 3500 ml. of dichloromethane and washed with 3 N aqueoushydrochloric acid, saturated aqueous sodium bicarbonate and sodiumchloride solutions. The organic phase was dried over anhydrous sodiumsulfate and evaporated to dryness to yield a crystalline product.. Gaschromatographic analysis indicated that it contained 61.9% of racemiccis Z-benzoyl-octahydro- 6(2H)-isoquinolone and 13% of recemic trans 2-benzoyl-octahydro-6(2H)-isoquinoline. The product was recrystallizedtwice from benzene to give racemic cis2-benzoyl-octahydro-6(2H)-isoquinolone having a melting point ofl47l48.5.

EXAMPLE 2 Preparation of racemic trans 2-benzoyl-octahydro-6(2H)-isoquinolone from racemic 2-benzoyll,3,4,7,8,8a-hexahydro-6( 2H)-isoquinolone To a solution containing 25.5 g. of racemic 2- benzoyl-l,3,4,7,8,8a-hexahydro-6( 2H )-isoquinolone in 1000 ml. of% ethanol wereadded 2.5 g. of 10% palladium on carbon catalyst and the mixture washydrogenated at room temperature and 3 atmospheres pressure until theuptake of hydrogen ceased. The catalyst was removed by filtration andwashed with 95% ethanol and dichloromethane. The crystallized wasevaporated to dryness to yield an oil which crystallized on triturationwith ether. The product was recrystallized twice from absolute ethanolto yield racemic trans 2- benzoyl-octahydro-6(2H)-isoquinolone, whichafter two additional recrystallizations from absolute ethanol, had amelting point of l57.5-159.

EXAMPLE 3 2 '-benzoyl-4( R ),5( R )-dimethyl- 7',8',8a(S )-octahydrosand2'- dioxolane-2,6( 5 H )-isoquinoline] To a solution containing 23.4 g.of rac. trans-2- benzoyloctahydro-6(lH)-isoquinolone in 2.1 of anhydrousbenzene was added 2.24 g. of p-toluenesulfonic acid and 9.83 g. of(-)-butane-2(R).3(R)-diol. The resulting solution was refluxed for 3hours and the water which formed was collected in a water separator.After the addition of 18 ml. of pyridine. the mixture was diluted to 4l. with benzene. washed four times with 100 ml. of water. dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. The lasttraces of pyridine were removed by codistillation with toluene in vacuo.The crystalline residue, 29.62 g., was fractionally crystallized byrepeating several times the following system:

29.62 g. mixture of ketals 6 hours reflux "with distilled petroleumether (b.p. 3060" C) \l lnsoluble part soluble partreorystalllrecrystallization Zatlon from from ethanol-water ether2'--Bcr1Z0yl-4(R), (R)-dimethyl- 2'-Ben7.oyl-4(R) 5(R)-dlmethyll, 2, 3,4 4a(R), 7, 8', 8a(R)- 1, 2 3, 4, 4'a(), 7, 8', 8'a(S)- EXAMPLE 4Preparation of 421(5),

6( 2H )-isoquinolone 8a(S)-2-benzoyloctahydro- A solution containing 2.5g. of 2-benzoyl-4(R),s(R)-' EXAMPLE 5 Preparation of 4a( R ),8a( R)-2-benzoyloctahydro- 6( 2H )-isoquinolone A solution containing 0.329g. of 2-benzoyl- 4(R),5(R)-dimethyl-1,2',3,4,4a(R),7,8,8a(R)-octahydrospiro[1.3-dioxolane-2,6'( SH )-isoquin0line] in 50 ml. ofacetic acid was heated at -l05 for 4 hours and 40 minutes. The reactionmixture was evaporated in vacuo diluted with 500 ml. of benzene. washedwith 50 ml. of 2N aqueous sodium carbonate and 3 times with 50 ml. ofwater. dried over anhydrous sodium sulfate and evaporated in vacuo toyield 0.256 g. of 4a( R ).8a( R )-2-benzoyloctahydro-6( 2H isoquinolonehaving a melting point of l51-153 (from absolute ethanol); [01],, 62.60(c 1.005. CHCl EXAMPLE 6 Preparation of racemic cis7-benzoyl-decahydro-2H- pyrido[3.4-d]-azepin-2-one from racemic cis 2-benzoyl-octahydro-6( 2H )-isoquinolone To a suspension containing 20.6g. of finely ground racemic cis 2-benzoyl-octahydro-6(2H)-isoquin0lonein 800 g. of polyphosphoric acid were added 10.0 g. of sodium azide, andthe mixture was stirred 16 hours at 5560. After cooling at roomtemperature, the reaction mixture was poured onto crushed ice. Theresulting solution was made alkaline with solid sodium carbonate at 0,and was extracted thoroughly with dichloromethane. The organic phase waswashed with water. dried over anhydrous sodium sulfate and evaporated todryness in vacuo. The oily residue crystallized on trituration withacetone. Fractional crystallization of the crystalline product fromacetone yielded cis 7-benzoyldecahydro-2H-pyrido[3,4-dlazepin-Z-one,which after one recrystallization from absolute ethanol and threerecrystallizations from acetone had a melting point of 167-168.5.

EXAMPLE 7 Preparation of racemic trans 7-benzoyl-decahydro-2H-pyrido[3,4-d]-azepin- 2-one from racemic trans 2- benzoyl-octahydro-6(2H )-isoquinolone To a mixture containing 5.15 g. of trans2-benzoyloctahydro 6(2H)-isoquinolone and 200 g. of polyphosphoric acidwere added 2.5 g. of sodium azide and the reaction mixture was stirredat 5560 for 16 hours. After cooling to room temperature, thepolyphosphoric acid was hydrolyzed by addition of ice. The resultingsolution was made alkaline with concentrated sodium carbonate solutionand extracted thoroughly with dichloromethane. The extract was washedwith water, dried over anhydrous sodium sulfate and evaporated todryness to yield 5.45 g. of crystalline racemic trans 7-benzoyl-decahydro-2H-pyridol3,4-dl-azepin-Z-onc. After recrystallizationfrom ethanol/ether it had a melting point of l87-l89.

EXAMPLE 8 Preparation of 5a( S ),9a( S )-7-benzoyldecahydro-2 H- pyrido[3,4-d lazepin-2-on'e To a mixture of finely ground 2.57 g. of4a(S),8a(S)- 2-benzoyloctahydro-6(2H)-isoquinolone and 100 g. ofpolyphosphoric acid was added 1.3 g. of sodium azide. The reactionmixture was stirred at 5560C. (bath) for 16 hours. cooled to roomtemperature and poured into ca. 380 g. of crushed ice. After the ice hadmelted. the resulting solution was made alkaline with 6N aqueous sodiumcarbonate (370 ml.) and extracted 3 times with 300 ml. of methylenechloride. -Methylene chloride extract was washed 3 times with 40 ml. ofwater, dried over anhydrous sodium sulfate and evaporated to dryness, togive 2.72 g. of crystalline 5a(S).9a(S)-7-benzoyldecahydro-2H-pyrido[3,4-dlazepin-2-one. From absolute ethanol itcrystallized with one mole of ethanol. m.p. 200203C., [01],, 37.83 (c1.0547, CHClg); on drying loses ethanol to give anhydrous form, m.p.90-100.

EXAMPLE 9 Preparation of racemicZ-benzoyl-l,2.3,4,7.8,9,9aoctahydro-6H-pyrido[3,4-d]azepin-6-one fromracemic Z-benzoyl-l ,3 ,4,7,8.8a-hexahydro-6( 2H isoquinolone To asuspension containing 1.02 g. of finely ground racemic 2-benzoyl-l .3,4,7.8,8a-hexahydro-6( 2H isoquinolone in 40 g. of polyphosphoric acidwas added 0.5 g. of sodium azide and the reaction mixture was stirred at120 for 30 minutes. After cooling to room temperature, ice was added.The resulting solution was made alkaline with saturated aqueous sodiumcarbonate at 0 and was extracted with dichloromethane. Thedichloromethane extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. The product was crystallizedby trituration with acetone to give racemicZ-benzoyl-l,2,3,4,7,8,9,9aoctahydro-6H-pyrido[3,4-d1azepin-6-one havinga melting point of 2l9221.

EXAMPLE Preparation of racemic cis 7-benzoyl-decahydro-2H-pyrido[3,4-d]azepin-2-one from racemic2-benzoyll.2.3,4,7,8,9,9a-octahydro-6H-pyrido[ 3,4-d1azepin- 6-one To asolution containing 5.4 g. of racemic2-benzoyll,2,3,4,7,8,9,9a-octahydro-6H-pyrido[ 3.4-d1azepin- 6-one in450 ml. of absolute ethanol were added 10 ml. of 3N aqueous hydrochloricacid and 5.4 g. of 5% rhodium on alumina catalyst. The reaction mixturewas hydrogenated at room temperature and atmospheric pressure until theuptake of hydrogen ceased. Thereafter. the catalyst was removed byfiltration and washed thoroughly with ethanol. The filtrate wasneutralized with 2N aqueous sodium carbonate and evaporated to a smallvolume in vacuo. The residue was extracted with 1000 ml. ofdichloromethane. The extract was washed with water, dried with anhydroussodium sulfate and evaporated to dryness. The non-crystalline productexhibited an lR-spectrum identical to that of the racemic cis7-benzoyl-decahydro-2H-pyrido[3.4-d1azepin- Z-one of Example 6, andafter being recrystallized twice from acetone. had a melting point ofl62l65.

EXAMPLE 11 Preparation of racemic cis l-benzoyl-3-(2-aminoethyl-4-piperidineacetic acid ethyl ester from racemic cis 287-benzoyl-decahydro-2H-pyrido[ 3.4-dlazepin-2-one A solution containing2.8 g. of racemic cis 7-benzoyldecahydro-2H-pyrido[3,4-dlazepin-2-one in500 ml. of 5% ethanolic hydrochloric acid was refluxed for hours.Thereafter. the solvent was removed by evaporation in vacuo. The residuewas taken up in 1200 ml. of dichloromethane. The resulting solution wasshaken with a solution containing 0.53 g. of sodium carbonate in 10 ml.of water. dried over anhydrous sodium sulfate and evaported to yieldoily racemic cis l-benzoyl-3( 2- aminoethyl)-4-piperidineacetic acidethyl ester.

EXAMPLE 12 Preparation of racemic trans l-benzoyl-3-(2-arninoethyl)-4-piperidineacetic acid ethyl ester from racemictrans7-benzoyl-decahydro-2H-pyrido[3.4- dlazepin-Z-onebenzoyl-3-(2-aminoethyl)-4-piperidine-acetic acid ethyl ester.

EXAMPLE 13 Preparation of racemic cis l-benzoyl 3 vinyl-4-piperidineactic acid ethyl ester (racemic benzoylmeroquinene ethylester) from racemic cis l-benzoyl-3-(2-aminoethyl)-4-piperidineaceticacid ethyl ester A mixture containing 1.91 g. of racemic cis 1-benzoyl-3-(Z-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.38 g. offormic acid and 1.05 g. of 37% formaldehyde was heated for 1 hour at100. After cooling to room temperature, 3.5 ml. of concentratedhydrochloric acid were added and the mixture thus obtained wasevaporated to dryness in vacuo. The residue was dissolved in 50 ml. ofwater. The solution was washed by shaking with ether. made alkaline toabout a pH 8 with 2 N sodium carbonate and extracted thoroughly withdichloromethane. The extract was washed with water, dried over anhydroussodium sulfate and evaporated to dryness in vacuo to give oily racemiccis l-benz0yl-3- (2-dimethylaminoethyl)-4-piperidineacetic acid ethylester. To the stirred solution containing this product in 10 ml. ofmethanol were added 2 ml. of 30% aqueous hydrogen peroxide at 0. Thereaction mixture was warmed to room temperature and stirred for 16hours. The excess of hyrogen peroxide was decomposed by addition ofplatinum black with stirring for 1 hour at 0. The platinum black wasseparated by filtration and washed with methanol. The filtrate wasevaporated to dryness in vacuo to yield racemic cis 1-benzoyl-3-(2-dimethylaminoethyl)-4-piperpidineacetic acid ethyl ester N-ozide as anoil. Heating of this product in vacuo at a temperature from 90 to C.over a period of 25 minutes yielded racemic N-benzoylmerquinene ethylester, which, after purification by preparative thin layerchromatography and recrystallization from hexane. had a melting point of6668.

EXAMPLE l4 preparation of racemic trans 1-benzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester from racemictrans 1-benzoyl-3-(2- aminoethyll-4-piperidineacetic acid ethyl ester Amixture containing 1.4 g. of racemic trans lbenzoyl-3-(Z-aminoethyl)-4-piperidineacetic acid ethyl ester, 1.4 g. of formic acidand 1.1 g. of 37% aqueous formaldehyde was heated at 95l00. The reactionmixture became a clear solution and a vigorous evolution of gasoccurred, which ceased after 1.5 hours. After cooling to roomtemperature, 1 ml. of concentrated hydrochloric acid was added and themixture was evaporated in vacuo. The residue was dissolved in 100 ml. ofwater, washed by shaking with ether, made alkaline with 2 N aqueoussodium carbonate and extracted thoroughly with dichloromethane. Theextract was dried over anhydrous sodium sulfate and evaporated to yieldracemic trans l-benzoyl-3-(2- dimethylaminoethyl)-4-piperidine aceticacid ethyl cstcr.

EXAMPLE Preparation of racemic trans 1-benzoyl-3-(2-dimethylaminoethyl)-4-piperidineacetic acid ethyl ester N-oxide fromracemic -dimethylaminoethyl)-lbenzoyl-3-( Z-dimethylaminoethyl )-4-piperidineacetic acid ethyl ester -dimethylaminoethyl)- EXAMPLE 16Preparation of racemic trans l-benzoyl-3-vinyl-4- piperidineacetic acidethyl ester from racemic trans 1-benzoyl-3-(Z-dimethyla-minoethyl)-4-piperidineacetic acid ethyl ester N-oxide A flask containing 0.63 g. ofracemic trans l-benzoyl- 3-(Z-dimethylaminoethyl)-4-piperidineaceticacid ethyl ester N-oxide was pyrolyzed at 90l20 for minutes. The productwas chromatographed on a 400 g. silica gel column with ether to yieldracemic trans lbenzoyl-3-vinyl-4-piperidineacetic acid ethyl ester as aglass.

EXAMPLE 17 Preparation of racemic cis7-benzoyl-l-nitrosodecahydro-2H-pyrido[3.4-d1azepin-2-one from racemiccis 7-benzoyl-decahydro-2H-pyrido[3,4- dlazepin-Z-one To a solutioncontaining 5.521 g. of nitrogen tetroxide in 360 ml. of carbontetrachloride at were added 9.84 g. of anhydrous sodium acetate. Themixture was allowed to warm to 0 and solution 710.88 g. of racemic cis7-benzoyI-decahydro-2H- pyrido-[3.4- d]azepin-2-one in 40 ml. ofdichloromethane was added with stirring. After 30 minutes at 0 themixture was poured into a slurry of ice and water. The resulting mixturewas placed in a separatory funnel and the or ganic phase was separated.The aqueous phase was extracted thoroughly with ice-colddichloromethane. The combined organic phases were washed with water.dried over anhydrous sodium sulfate. and evaporated to dryness at 0 C.in vacuo to yield oily racemic cis 7- benzoyl-l-nitroso-decahydro-2H-pyridol 3.4-d ]azepin- 2-one.

EXAMPLE 18 Preparation of racemic trans7-benzoyl-l-nitrosodecahydro-2H-pyrido[3,4-d]azepin-2-one from racemictrans 7-benzoyl-decahydro-ZH-pyrido 3,4- d]azepin-Z-one To ml. ofcarbontetrachloride solution containing 1.31 g. of nitrogentetroxide at70 were added 2.46 g. of anhydrous sodium acetate. The mixture wasallowed to warm to 0, and 2.6 g. of racemic trans 7-benzoyl-decahydro-ZH-pyrido[3,4-dlazepin-2-one in 50 ml. ofdichloromethane were added with stirring. The reaction mixture wasmaintained at 0 for 30 minutes. Thereafter, it was poured into a slurryof ice and water, transferred to a separatory funnel and the organicphase was removed. The aqueous phase was extracted with three 250 ml.portions of dichloromethane. The organic phases were combined, washedwith water, dried over anhydrous sodium sulfate and evaporated todryness to yield racemic trans7-benzoyl-lnitroso-decahydro-ZH-pyrido[3,4-dlazepin-2-one, a greenyellow powder. All operations were carried out at 0.

EXAMPLE 19 Preparation of racemic N-benzoyl-meroquinene [racemic cisl-benzoyl-3-vinyl-4-piperidineacetic acid] from racemic cis7-benzoyl-l-nitroso-decahydro-2H- pyridol 3.4-d lazepin-Z-one Theracemic cis 7-benzoyl-l-nitroso-decahydro-2H- pyrido-l3,4-dlazepin-2-onefrom Example 17 was placed in a flask fitted with a reflux condenser andheated under nitrogen on an oil bath maintained at for about 1 hour. Theresidue was taken up in 50 ml. of 1N potassium hydroxide, diluted with50 ml. of water and washed by shaking with ether. The aqeuous phase wasneutralized with 50 ml. of 1N hydrochloric acid and extracted withether. The ether phase was washed with water, dried over anhydrousmagnesium sulfate and evaporated to dryness to yield racemic N-benzoyl-meroquinene, as an oil.

EXAMPLE 20 Preparation of racemic trans l-benzoyl-3-vinyl-4-piperidineacetic acid from racemic trans7-benzoyll-nitroso-decahydro-2H-pyrid0-[3,4-dlazepin-2-one The productof Example 18, i.e., racemic trans 7- benzoyl-l-nitroso-decahydro-2H-pyrido[ 3 ,4-d ]azepin- 2-one was heated at 125under nitrogen for 1 hour. The product was taken up in 13 ml. of lNaqueous potassium hydroxide and 30 ml. of water, washed with four l ml.portions of ether. neutralized with 13 ml. of IN aqueous hydrochloricacid and extracted with four 200 ml. portions of ether. The etherealextract was washed with 70 ml. of water. which was combined with aqueousphase. dried over anhydrous magnesium sulfate and evaporated to yieldoily racemic trans lbenzoyl-3-vinyl-4-piperidineacetic acid.

EXAMPLE 2] Preparation of l-benzoyl-3( S )-vinyl-4(S piperidineaceticacid To 143 ml. of 0.l5M solution of dinitrogen tetroxide incarbontetrachloride immersed in a dry ice-acetone bath were added 3.51g. of anhydrous sodium acetate, and the mixture was allowed to warm to0C. A solution containing 3.86 g. of 5a(S),9a(S)-7-benzoyldecahydro-2H-pyrido[3,4-dlazepin-2-one in 50 ml. of methylene chloride was addedwith stirring. and after standing for 30 minutes at 0C. the mixture waspoured into a slurry of ice and water (280 ml.). The resulting mixturewas placed in a separatory funnel and the organic phase was removed. Theaqueous phase was extracted 3 times with 430 ml. of methylene chloride.The combined organic phases were washed with 100 ml. of water, driedover anhydrous sodium sulfate and evaporated in vacuo. All theseoperations were carried out at 0C. It gave quantitative yield of paleyellow powder, 1- nitroso-5a(S),9a(S)-7-benzoyldecahydro-2H-pyrido[3,4-dlazepin-Z-one, which was processed immediately further.

The nitroso product was heated at 125C. (bath) under nitrogen. lnitiallyviolent reaction ceased slowly after 30 minutes. The residue (3.92 g.)was taken up in 19 ml. of IN aqueous potassium hydroxide, diluted withwater (60 ml.) and washed 4 times with I50 ml. of ether. It was thenneutralized with 19 ml. of 1N aqueous hydrochloric acid and extracted 4times with 300 ml. of ether. The ethereal extract was washed with 60 ml.of water. dried over anhydrous magnesium sulfate and evaporated in vacuoto give 2.34 g. of oily lbenzoyl-3(S)-vinyl-4(S)-piperidineacetic acidwhich contained minor impurities (tlc).

EXAMPLE 22 Preparation of racemic N-benzoylmeroquinene methyl ester[racemic cis l-benzoyl-3-vinyl-4- piperidineacetic acid methyl ester]from racemic N- benzoylmeroquinene [racemic cis l-benzoyl-3-vinyl-4-piperidineacetic acid] To a stirred solution containing 5.29 g. ofracemic N- benzoylmeroquinene in 500 ml. of ether was added I g. ofdiazomethane in 50 ml. of ether. Stirring was continued for minutes. Theexcess diazomethane was decomposed by a dropwise addition of glacialacetic acid until the yellow color disappeared. The reaction mixture wasdiluted to 1000 ml. with ether. washed with 2N sodium carbonate andwater. dried over anhydrous magnesium sulfate and evaporated in vacuo toyield oily N-benzoylmeroquinene methyl ester.

EXAMPLE 23 Preparation of rac. trans l-benzoyl-3-vinyl-4-piperidineacetic acid methyl ester To the solution of 0.476 g. of rac.trans l-benzoyl-3- vinyl-4-piperidineacetic acid in 4 ml. of methanolwas added 9 ml. ofdiazomethane solution in ether (concentration ca. 3g./130 ml.). After few minutes an additional 9 ml. of diazomethanesolution was added. and then stirred at room temperature for l hour. Theexcess of diazomethane was destroyed by addition of several dropsglacial acetic acid. and thus resulted mixture was evaporated to drynessin vacuo. leaving 0.5 g. of oily residue. The crude product waschromatographed on 7 Brinkman silica gel preparative plates withbenzeneether 1:] mixture. Elution with ethanol gave 0.20]

g. of oily rac. trans l-benzoyl-3-vinyl-4- piperidineacetic acid methylester.

EXAMPLE 24 Preparation of l-benzoyl-3(S )-vinyl-4( S piperidineaceticacid methyl ester To a cooled solution containing 2.34 g. of l-benzoyl-3(S)-vinyl-4(S)-piperidineacetic acid in 20 ml. of methanol was added 20ml. of diazomethane solution in ether (concentration ca 3 g./ l 30 ml.After few minutes an additional 20 ml. of diazomethane solution wasadded and then stirred at room temperature for 5 minutes. The excess ofdiazomethane was destroyed by addition of several drops of glacialacetic acid, and thus resulted mixture was evaporated to dryness invacuo. leaving 2.9 g. of oil residue. The crude product waschromatographed on 26 Brinkman silica gel preparative plates withbenzene-ether 1:1 mixture. Elution with 95% ethanol gave l.059 g. ofoily l-benzoyl-3(S)-vinyl- 4(S)-piperidineacetic acid methyl ester,[01],, l.6l (c 1.1 193, CHCla).

EXAMPLE 25 Preparation of racemic cis 6-methoxy-4- {3-[ l-benzoyl-3-vinyl-4-piperidyl]-2-oxopropyl}quinoline from 6- methoxylepidine andracemic N- benzoylmeroquinene methyl ester [cis l-benzoyl-3-vinyl-4-piperidineacetic acid methyl ester] To a solution containingabout 0.032 mole of lithium diisopropyl amide [prepared at 20 in anatmosphere of dry nitrogent by the addition of 6 ml. of drydiisopropylamine to 15.5 ml. of phenyllithium in benzene-ether(7:3)]were added dropwise a solution containing 5.6 g. of6-methoxylepidine in 60 ml. of anhydrous tetrahydrofuran. The reactionmixture was stirred for 20 minutes. To the practically homogeneous,dark-brown solution of 6-methoxylepidyl lithium thus obtained was addeddropwise over a period of 20 minutes a solution containing 4.6 g. ofracemic N-benzoylmeroquinene methyl ester in 60 ml. of anhydroustetrahydrofuran. After the addition was completed, stirring wascontinued for 60 minutes. During the whole operation the reactiontemperature was maintained at 20. Thereafter. ice and water were addedand the reaction mixture was neutralized to a pH 8 with acetic acid and10% sodium bicarbonate. The aqueous phase was extracted thoroughly withether. The ethereal extract was washed with water, dried over anhydrousmagnesium sulfate and evaporated. The residue was adsorbed on a 550 g.neutral alumina column (activity ll). After elution of unreactedo-methoxylepidine with benzene, the amorphous racemic cis6-methoxy-4-{3-[ l-benzoyl-3-vinyl- 4-piperidyll-2-oxopropyl}quinolinewas eluted with benzene containing 20-50% of ethyl acetate.

EXAMPLE 26 Preparation of 6-methoxy-4{3-[l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2oxopropyl quinoline from 6- methoxy-lepidine andN-benzoyl meroquinene ethyl ester To a solution of ca. 0.07 mole oflithium diisopropyl amide [prepared by addition of ml. of drydiisopropyl amine in 10 ml. of toluene to 35 ml. of ca. 2 molar n-butyllithium in hexane, at 78 under nitrogenlwas added dropwise (10 min.)with stirring a solution of 13 g. (0.075 mole) of 6-methoxy-lepidine in120 ml. of tetrahydrofuran. The mixture was stirred at 78 for 30 min.,and there was added dropwise (10 min.) a solution of 10.5 g. I (0.0345mole) of N- benzoylmeroquinene ethyl ester in 150 ml. oftetrahydrofuran. Stirring was continued at -78 for 30 min. The coolingbath was removed and the stirring was continued for another 30 min.Water was added, the aqueous layer was neutralized (pH ca. 8) withacetic acid and extracted thoroughly with ether. The ethereal phase waswashed (water), dried (magnesium sulfate) and evaporated in vacuo. Theresidue was absorbed on 600 g. of neutral alumina, activity ll; afterelution of excess -methoxy-lepidine with benzene, elution withbenzene-ethyl acetate l:l afforded amorphous 6methoxy4{3-[ l-ben2oyl-3(R)-vinyl-4(S)-piperidyl ]-2-oxopropyl}-quinoline; [01],, 27.3 (c 1.205;chloroform).

EXAMPLE 27 Preparation of 6-methoxy-4{-3-[1-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl quinoline from 6- methoxylepidine andN-benzoyl-meroguinene methyl ester A condensation reaction carried outin analogous way as in Example 30a with 1.8 g. (0.0104 mole) of 6-methoxylepidine and 1.49 g. (0.0052 mole) of N- benzoyl-meroquinenemethyl ester (phenyl lithium was used instead of n-butyl lithium)yielded after a similar technique and separation by columnchromatography 6-methoxy-4 {-3-[ l-benZoyl-3( R )-vinyl-4(S)-piperidyl]-2-oxopropyl}-quinoline.

EXAMPLE 28 Preparation of 7-chloro-4-{3-ll-benzoyl-3(R)-vinyl-4(S)-piperidyll-2-oxopropyl -quinoline from 7- chlorolepidine andN-henzoyl-meroquinene ethyl ester (ca. hexane] Stirring To a dry icecooled solution of ca. 0.061 mole of lithium diisopropyl amide [preparedin an atmosphere of dry nitrogen by addition of 10 ml. (ca. 0.07 mole)of diisopropylamine in 30 ml. oftetrahydrofuran to 30 ml. of ca. 2Mn-butyllithium in hexane] was added dropwise min.) a solution of 11 g.(0.061 mole) of 7- chlorolepidine in 60 ml. of tetrahydrofuran. Theresulting brown suspension was stirred at 78 for min., then there wasadded a solution of 9.2 g. (0.0305 mole) of N-benzoyl-meroquinene ethylester in 60 ml. of tetrahydrofuran. Stirring was continued at -78 for 40min. After removing the cooling bath, stirring was continued for another40 min. After addition of 50 ml. of water, the mixture was neutralizedwith acetic acid and the pH was adjusted to ca. 8 by addition of 10%sodium bicarbonate. The aqueous phase was extracted thoroughly withether. the ethereal phases were washed (2 X 10% sodium bicarbonate,dried (magnesium sulfate) and evaporated to dryness. Crystallizationfrom acetone-ether afforded crystalline 7-chloro-4-i3-llbenzoyl-3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline; the motherliquor was absorbed on 300 g. of neutral alumina, activity II. andelution with ethyl acetate afforded additional amounts of 7-chloro-4-{3-[ l-benzoyl-3(R)-vinyl-4( S)-piperidyl I-2-oxopropyl}quinoline; m.p. 147-l48 (acetone); [1110 38.7 (c. 1.00,chloroform).

EXAMPLE 29 Preparation of epimeric 7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl -quinolines from 7-chloro-4-{3-[l-benzoyl-3(R)-vinyl-4(S)- piperidyl]-2-oxopropyl}quinoline To an icecold solution of 7.84 g. (0.018 mole) of 7- chloro-4-{3-ll-benzoyl-3(R)-vinyl-4(S )-piperidyl ]-2- oxopropyl}quinoline in 200 ml.of methanol was added excess solid sodium borohydride, and the solutionwas stirred for 60 min. at 0. Fifty ml. of water was added, the methanolwas evaporated in vacuo, and the aqueous residue was extractedthoroughly with dichloromethane. The organic extracts were washed (sat.sodium chloride); dried (sodium sulfate) and evaporated to give epimeric7-chloro-4-{3[ l-benzoyl-3(R)-vinyl- 4(S)-piperidyll-2-hydroxypropylquinolines. The crude, dried product was dissolved in 200 ml. of drytoluene and 50 ml. of dry tetrahydrofuran, the solution was cooled to-78, and 25 ml. (ca. 0.04 mole) of a 25% solution of diisobutyl aluminumhydride in toluene was added dropwise l 5 min.). The homogeneoussolution was stirred at 78 for 40 min., 60 ml. of methanolwater (1:1)was added, and stirring was continued for 20 min. at -78, then for 2hrs. without cooling. The inorganic precipitate was removed byfiltration and washed thoroughly with methanol. The combined filtrateswere evaporated to dryness and the residue was partitioned between etherand 1N hydrochloric acid. The acidic extracts were made alkaline (conc.ammonia) and extracted thoroughly with dichloromethane. The organicphase was washed (sat. sodium chloride), dried (sodium sulfate) andevaporated to give amorphous epimeric 7-chloro-4-{3-[3(R)-vinyl4(S)-piperidyll-2-hydroxypropyl}quinolines.

EXAMPLE 30 Racemic trans 6.8-dimethoxy-4-[ 3-( 3-ethyl-4-piperidyl)-2-oxopropyl]quinoline from 6,8- dimethoxy lepidine andracemic trans 3-ethyl-4- piperidineacetic acid ethyl ester To a dry icecooled solution of ca. 0.036 mole of lithium diisopropyl amide (preparedby addition of 6 ml. of diisopropyl amine in 10 ml. of toluene to 16 m1.of ca. 2M n-butyl lithium in hexane, at 78 in an atmosphere of drynitrogen) was added dropwise (5 min.) with stirring a solution of 7.3 g.(0.036 mole) of 6,8-

dimethoxy-lepidine in 50 ml. of dry tetrahydrofuran. The inhomogeneousmixture containing 6,8-dimethoxy lepidyl lithium was stirred for 15min., then a solution of 3.65 g. (0.018 mole) of trans 3-ethyl-4-piperidineacetic acid ethyl ester in 50 ml. of tetrahydrofuran was addeddropwise (30 min.). Stirring was continued for 60 min. at 78. 50 Ml. ofwater was added, the aqueous phase was neutralized with acetic acid (pHca. 8) and extracted thoroughly with ether. The ethereal phase waswashed (ca. 1% sodium bicarbonate solution), dried (sodium sulfate), andevaporated to give a crude product (ca. 6 g.), containing only traces ofketone 4 as indicated by thin layer chromatography. The combined aqueousphases were saturated with sodium chloride and extracted thoroughly withchloroform-ethanol (19:1), the organic extracts were dried (sodiumsulfate) and evaporated in vacuo to give g. (ca. in vacuo of practicallypure racemic trans 6,8-dimethoxy-4 -[3-(3-ethyl-4-piperidy|)-2-piperidyl]-2-oxopropyl} quinoline from 6- methoxylepidine andmeroquinene ethyl ester [3(R)- vinyI-4(S)-piperidineacetic acid ethylester] To a solution containing about 0.034 mole of lithium diisopropylamide [prepared at 80 in an atmosphere of dry nitrogen by addition of 6ml. of dry diisopropylamine to 16 ml. of about 2.14 molar phenyllithiumin benzene-ether (7:3)] was added dropwise a solution containing 6 g. of6-methoxylepidine in about 25 ml. of anhydrous tetrahydrofuran and thereaction mixture was stirred at 0 for 20 minutes. To the practicallyhomogeneous, dark-brown solution of 6-methoxylepidyl lithium thusobtained, was added dropwise a solution containing 3.5 g. of meroquineneethyl ester in 40 ml. of dry tetrahydrofuran with stirring at 0 for 60minutes. After the addition of 50 ml. of water the reaction mixture wasneutralized with acetic acid-sodium acetate to pH=9 and extractedthoroughly with ether. The ethereal extract was washed with water, driedover anhydrous magnesium sulfate and evaporated. The residue wasabsorbed on a 350 g. neutral alumina column (activity 11) after elutionof unreacted 6- methoxylepidine with dichloromethane, amorphous 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline waseluted with dichloromethane containing 1 to of methanol.

EXAMPLE 32 Preparation of 7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyll-Z-oxopropyl} quinoline from 7- chlorolepidine and meroquineneethyl ester [3(R)- vinyl-4(S)-piperidineacetic acid ethyl ester] To asolution containing about 0.0075 mole of lithium diisopropylamide[prepared in an atmosphere of dry nitrogen by addition of 1.3 ml. of drydiisopropylamine in 4 ml. of anhydrous tetrahydrofuran to 3.5 ml. ofabout 2.1 molar phenyllithium in benzene-ether (7:3)], cooled on a DryIce bath, was added dropwise with stirring a solution containing 1.33 g.of dry 7- chlorolepidine in 30 ml. of anhydrous tetrahydrofuran. Thereaction mixture was stirred at 75 for minutes. To the stirred,practically homogeneous, reddishbrown solution of 7-ch1orolepidyllithium thus obtained, was added dropwise a solution containing 0.70 g.of dry meroquinene ethyl ester in 20 ml. of anhydrous tetrahydrofuran.The dry-ice bath was removed and the solution was stirred at to +20 for3 hours. After the addition of 10 ml. of water, the reaction mixture wasneutralized (pH about 8) by addition of acetic acid and 10% sodiumbicarbonate, and extracted thoroughly with ether. The ethereal extractswere washed with water, dried over anhydrous magnesium sulfate andevaporated. The residue, a yellow oil, was adsorbed on a 70 g. neutralalumina (activity 11) column. After elution of unreacted7-chlorolepidine with dichloromethane, yellow amorphous 7-chloro-4-{3-[3(R)-vinyl-4(S)-piperidyll'2-oxopropyl} quinoline was eluted withdichloromethane containing 2 to 10% of methanol. The monohydrochlorideof 7-chloro-4-{3- [3(R)-vinyl-4(S)-piperidyl]-2-oxopropyl} quinoline wasrecrystallized from methanolacetone having a melting point of 236237(dec.), [01],, 26.9 (c. 1.02 CH OH).

EXAMPLE 33 Preparation of epimeric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyll-2-hydroxypropyl} quinolines from recemic cis6-methoxy-4-(3-[l-benzoyl-3-vinyl-4- piperidyll-Z-oxopropyl) quinolineTo a stirred solution containing 2.8 g. of racemic cis 6-methoxy-4-{3-[lbenzoyl-3-vinyl-4-piperidyl]-2- oxopropyl}-quinoline in ml. of drytoluene at 0. was added dropwise a solution containing 25% diisobutylaluminum hydride in toluene. while the course of the reaction waschecked by tLc. After 12 quinolines were added, the reaction wasquenched by the addition of 10 ml. of an ice cold mixture ofwater-methanol (1:1 The resulting mixture was stirred at 20. The aluminawhich precipitated was then removed by filtration, washed thoroughlywith methanol, and the combined filtrates were evaporated to dryness.The residue was dissolved in dichloromethane, washed with 1 N sodiumhydroxide and water, dried over anhydrous sodium sulfate and evaporated.The product, racemic epimaric cis 6-methoxy-4-3-[3-vinyl-4-piperidyl1-2- hydroxypropyl was dissolved in 40 ml. ofacetone, and added to the solution containing 1 g. of dibenzoyl-(d)-tartaric acid in 10 ml. of methanol. Crystallization yielded thecorresponding dibenzoyl-(d)-tartrate. The mother liquor was converted tothe free base which was purified by filtration on a 20 g. neutralalumina column (activity 11). Elution with dichloromethane-methanol (9:1gave additional product which could not be crystallized as the neutraldibenzoyl-(d)-tartrate.

To complete resolution, the above-mentioned crystallinedibenzoyl-(d)-tartate was recrystallized 4 times from methanolacetone togive the neutral dibenzoyld)-tartrates of the epimeric6-methoxy-4-{3-[3(R)- vinyl-4(S)-piperidyl]-2-hydroxypropyl}quinolineshaving a melting point of l89-l90; [01],, 27.4 (c 0.82. methanol).

EXAMPLE 34 Racemic, epimeric trans 6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)-2-hydroxypropyl]quinolines from racemic trans6,8-dimethoxy-4-[3-(3-ethyl-4-piperidyl)- 2-oxopropyl1quinoline To astirred, ice cold solution of g. (0.014 mole) of racemic trans6,8-dimethoxy-4[3-( 3-ethy1-4- piperidyl)-2-oxopropyl]quinoline in 150ml. of methanol was added 0.9 g. of solid sodium borohydride. Afterstirring for 60 min.. 50 m1. of water was added and the methanol wasremoved by evaporation. The aqueous residue was saturated with sodiumchloride and extracted thoroughly with chloroform-ethanol (9:1 Theextracts were dried (sodium sulfate) and evaporated to give 5 g.(quantitative recovery) of racemic. epimeric trans6,8-dimethoxy-4-[3-(3-ethyl-) 4-piperidyl)-2- hydroxypropyl}quinolinesas a crude oil.

EXAMPLE 35 Preparation of epimeric 6-methoxy-4-{3-[3(R)'viny1-4(S)-piperidy1-2-hydroxypropyl}quinolines from 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline Asolution containing 1,8 g. of 6-methoxy-4- {3-[3(R)-viny1-4(S)-piperidyl]-2-oxopropyl} quinoline in 20 m1. of methanolwas added to an ice cold solution containing 1 g. of sodium borohydridein 100 ml. of methanol. The solution was stirred at 0? to 20 for 90minutes. After addition of 50 ml. of water, the methanol was removed bydistillation. The remaining aqueous phase was extracted withdichloromethane. The extract was washed with 1N aqueous sodium hydroxideand water, dried over anhydrous sodium sulfate and evaporated todryness. The residue was dissolved in a small volume of methanol, andadded to a solution containing 0.98 g. of dibenzoyl-(d)-tartaric acid inacetone. Crystallization yielded the neutral dibenzoy1-(d)- tartrates ofthe epimeric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidy1]-2-hydroxypropyl}quinolines having a melting point ofl89l90 after recrystallization from ethanol-acetone; [a],, =27.0 (c1.09, methanol).

The free base, epimeric 6-methoxy-4{3-[3-(R)-vinyl-4(S)-piperidyll-2-hydroxypropyl}quinolines, was obtained as a viscous.colorless oil; [01],, 39.6 (c 1.425, chloroform).

EXAMPLE 36 Preparation of epimeric 7-chloro-4-{3-[3(R)-viny1-4(S)-piperidyl]-2-hydroxypropy1} quinolines from 7-chloro-4{3-[3(R)-vinyl-4(S)-piperidyl]-2- oxopropyl}quinoline To a stirred, icecold solution containing 1.98 g. of

oxopropyl}quinoline in 60 ml. of methanol was added 1 g. of sodiumborohydride in portions. After stirring for 10 minutes, ml. of waterwere added and the methanol was evaporated. The remaining mixture wasmade alkaline with 1N sodium hydroxide and extracted thoroughly withdichloromethane. The extract was washed with water, dried over anhydroussodium sulfate and evaporated to yield 1.61 g. of epimeric 7hydroxypropyl}quinolines. The neutral dibenzoyl-(d)- tartrate had amelting point of 198-199 after recrystallization fromdichloromethane-methanol.

EXAMPLE 37 Preparation of Epimeric 6-methoxy-4-{3-[l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2- hydroxypropyl} quinolines fromo-methoxylepidine and l-benzoyl-3(R)-viny1-4(S)- piperidineacetaldehydeTo ca. 0.0055 mole of lithium diisopropyl amide [prepared in anatmosphere ofdry nitrogen by addition of 0.8 ml. (ca. 0.06 mole) ofdiisopropyl amine to 2.6 m1. of 2.14 M phenyl lithium in hexane] wasadded with stirring a solution of 0.95 g. (0.0055 mole) of 6-methoxylepidine in 7 m1. of benzene and 25 m1. of letrahydrofu ran.After stirring at room temperature for 20 minutes a solution of 0.95 g.(0.0037 mole) of 1- benzoyl-3(R)-vinyl-4(S)-piperidineaceta1dehyde in 14ml. of tetrahydrofuran was added dropwise (30 min.), and the resultingmixture was stirred at room temperature for 15 hours. Water (50 ml.) wasadded, the aqueous phase was extracted thoroughly with ether. Theethereal phase was washed (2 X aq. sodium chloride), dried (sodiumsulfate) and evaporated to dryness. The crude product (2.4 g.) wasabsorbed on 100 g. of neutral alumina, activity 11, and elution withethyl acetate containing 1% of methanol afforded 0.88 g. (55%) ofepimeric 6-methoxy-4-{3-l l-benzoyl-3(R)-vinyl- 4(8)-piperidyll-2-hydroxypropyl }quinolines as a colorless oil.

EXAMPLE 38 Preparation of Epimeric 6-methoxy-4-{3-l3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl} -quino1ines from epimeric6-methoxy-4-{3-[ l-benzoyl-3( R)-vinyl-4(S)-piperidyl1-2-hydroxypropyl}-quinolines To a solution of 0.145 g.(0.00033 mole) of epimeric 6-methoxy-4-{3-[ l-benzoyl-3(R)-vinyl-4(S)-piperidyl]-2-hydroxypropyl }-quinolines in 20 m1. of tetrahydrofuran wasadded 0.008g. (0.0015 mole) of sodium aluminum hydride, and the mixturewas stirred at room temperature for min. Ca. 20 ml. of 1N sodiumhydroxide was added, the aqueous phase was extracted thoroughly withether, the ethereal extracts were washed with water, dried (sodiumsulfate) and evaporated to give 0.11 g. (over recovery) of crudeepimeric 6-methoxy-4{3-[3(R)-viny1-4(S)-piperidyl]-2-hydroxypropyl}quinolines.

EXAMPLE 39 Preparation of epimeric 6-methoxy-4-{3-l3(R)-vinyl-4(S)-piperidyl]-2-acetoxypropy1} quinolines from epimeric6-methoxy-4-{3-[3(R)-vinyl-4(S)- piperidyl]-2-hydroxypropy1}quinolinesTo a solution containing 1.15 g. of epimeric 6-methoxy-4-{3-[3(R)-vinyl-4(S)-piperidy1]-2- hydroxypropyl}quinolines in40 ml. of glacial acetic acid were added 4 m1. of freshly distilledborontrifluoride etherate. The solution was kept at 50 for 18 hours.Thereafter, the reaction mixture was concentrated in vacuo to about 10ml., and, after addition of ice, neutralized (pH ca. 8) with 6N sodiumhydroxide. The ice cold, alkaline phase was extracted thoroughly withdichloromethane. and the extracts were washed with water, dried overanhydrous sodium sulfate and evaporated to yield epimeric6-methoxy-4-{3-[3(R)-vinyl-

1. AN EPIMERIC COMPOUND OF THE FORMULA
 2. Epimers in accordance withclaim 1, wherein R1 is methoxy; R2 is vinyl; R5 is methyl and m is 1,i.e., epimeric 6-methoxy-4-(3-(3(R)-vinyl-4(S)-piperidyl)-2 epsilon-acetoxypropyl)quinolines.
 3. Epimers in accordance with claim 1,wherein R1 is chloro; R2 is vinyl, R5 is methyl and m is 1, i.e.,epimeric 7-chloro-4(3-(3(R)-vinyl-4(S)-piperidyl)-2 epsilon-acetoxypropyl)quinolines.
 4. Epimers in accordance with claim 1,wherein R1 is chloro; R2 is vinyl; R5 is methyl and m is 2, i.e.,epimeric 6,8-dichloro-4-(3-(3(R)-vinyl-4(S)-piperidyl)-2 epsilon-acetoxypropyl) quinolines.
 5. An epimeric compound of the formula